PROJECT SUMMARY As estimated by the National Cancer Institute (NIH/NCI), there are more than 900,000 people living with melanoma in the USA. Despite recent advances in melanoma drug discovery, the average overall survival of patients with late stage metastatic melanoma is ~3 years. Instances of complete response are very rare, therefore, more life-prolonging therapies are needed. This suggests a need for new approaches and targets for melanoma drug discovery. We discovered a novel class of anti-melanoma compounds that potentiate autophagy leading to cell death. Preliminary results in different 2D and 3D cultures of melanoma cells, including BRAF- and NRAS-mutants, demonstrated the efficacy of our leads 2155-14 and 2155-18 comparable to the FDA-approved melanoma drug vemurafenib and the lack of toxicity to non-melanoma cells and a mouse model. Target identification studies revealed that 2155-14 binds to three proteins (DDX1, hnRNPA2/B1, and hnRNPH2) that were not previously considered for melanoma drug discovery. Mechanism of action studies suggest that binding of probes specifically to hnRNPH2 leads to an autophagic cell death in melanoma cells with different mutational backgrounds. This suggests an exciting potential for novel target(s) for broad-spectrum melanoma therapy. The overall aim of this project is to evaluate efficacy of novel anti-melanoma compounds in BRAF and NRAS mutant animal models of melanoma. Our team is uniquely positioned to achieve these goals due to expertise in cancer biochemistry and drug/probe discovery, and animal models. Our expected long-term outcome is to develop safe therapy for melanoma.